Approaches to the Synthesis of a Water‐Soluble Carboxy Nitroxide

Abstract

The robust and diversely useful isoindoline nitroxide, 5‐carboxy‐1,1,3,3‐tetramethylisoindolin‐2‐yloxyl (1; CTMIO), has previously been synthesised in low‐to‐moderate yields from phthalic anhydride (3). Recent interest in its biological potential as a potent antioxidant and in other areas has seen an increased demand for its production. Herein, three new synthetic routes to CTMIO are presented and their efficiencies assessed. Two routes, via the nitrile 9 and the formyl compound 11, derive from 5‐bromo‐1,1,3,3‐tetramethylisoindoline (6). The third approach starts from the readily accessible starting material, 4‐methylphthalic anhydride (12), and proceeds by a methylarene oxidation with potassium permanganate. The three new approaches yield CTMIO in comparable overall yields (16–18 %); however, the synthetic efficiency is most improved when employing the nitrile intermediate 9.

BODIPY‐Based Profluorescent Probes Containing Meso‐ and β‐Substituted Isoindoline Nitroxides

“…General Methods: All air‐sensitive reactions were carried out under an atmosphere of ultra‐high purity argon. 4,4‐Difluoro‐2‐iodo‐1,3,5,7‐tetramethyl‐8‐phenyl‐4‐bora‐3a,4a‐diaza‐s‐indacene ( 5 ), 4,4‐difluoro‐2,6‐diiodo‐1,3,5,7‐tetramethyl‐8‐phenyl‐4‐bora‐3a,4a‐diaza‐s‐indacene, 4,4‐difluoro‐2‐iodo‐1,3,5,7‐tetramethyl‐8‐phenyl‐6‐(phenylethynyl)‐4‐bora‐3a,4a‐diaza‐s‐indacene ( 8 ), 5‐formyl‐1,1,3,3‐tetramethylisoindolin‐2‐yloxyl ( 11 ),, and 5‐ethynyl‐1,1,3,3‐tetramethylisoindolin‐2‐yloxyl ( 6 ) were prepared by using established procedures. All other reagents were purchased from commercial suppliers and used without further purification.…”

Synthesis and Evaluation of Ciprofloxacin-Nitroxide Conjugates as Anti-Biofilm Agents

“…For these reasons, we chose to generate our first generation of ciprofloxacin-nitroxide hybrids by tethering nitroxides to the secondary amine of the piperazine ring of ciprofloxacin, using reductive amination chemistry [41] to generate a ciprofloxacin-nitroxide conjugate connected via a tertiary amine linkage. The cyclic nitroxides 4-oxo-2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPONE) 6 and the more rigid 5-formyl-1,1,3,3-tetramethylisoindolin-2-yloxyl (FTMIO) 12 [42] were selected as the nitroxide coupling partners as both these nitroxide structures contain bis( tert -alkyl) groups on the carbon atoms α to the nitroxide, making them highly resistant to degradation through disproportionation [43]. In addition to this, both of the structural piperidine and isoindoline cores have been previously shown to possess dispersal activities in bacterial biofilms [27].…”

Advances in the synthesis of nitroxide radicals for use in biomolecule spin labelling

“…24 An alternative approach to functionalized isoindolines involves direct bromination of the benzene ring (4344), which enables the introduction of a variety of substituents including water-solubilizing carboxylic acid 45, which could be introduced by lithiation / quench with CO2, or cyanation (46) followed by nitrile hydrolysis. 25 Cyclic N,N-and N,O-acetal nitroxides benefit from concise, modular preparation sequences. For example, oxazolidine nitroxide 47 (Scheme 5b) was assembled by condensation of aminoalcohol 48 with ketone 49; N-oxidation of the resulting oxazolidine followed by phthalimide deprotection gave 47.…”